Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
  • C07H15/02—Acyclic radicals, not substituted by cyclic structures
  • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

• the present invention relates to a novel compound useful as a treating agent for multiorganic insufficiencies. More particularly, it relates to a novel amino sugar derivative which inhibits TNF induction of human macrophage by endotoxin and is therefore used in the treatment of multiorganic insufficiencies.
• Acute pulmonary lesions or multiorganic insufficiencies are diseases of extremely high death ratio, and intensive studies have been given to these diseases in terms of pathology, early diagnosis and treatment. The onset of these diseases often follows or accompany infectious diseases. In such cases, endotoxin is considered to play a major role. Endotoxin is known to activate phagocytes, such as macrophage, and various cytokines which are derived through the activation are considered to participate in the symptoms.
• Cytokines deeply concerned with pulmonary lesions or multiorganic insufficiencies include TNF (tumor necrosis factor), interleukins, etc. These cytokines have been confirmed to induce an acute pulmonary lesion in animal experiments.
• the present invention relates to a compound represented by formula (I): wherein R1 represents -CO-Z1-N(Z11)-CO-Z2-H or -CO-Z3-H, wherein Z1, Z2, and Z3 each represent an alkylene group having from 1 to 20 carbon atoms, a phenylene group, or a combination thereof, and Z11 represents a hydrogen atom, an alkyl group having from 1 to 20 carbon atoms which may be substituted with a phenyl group, a phenyl group which may be substituted with an alkyl group having from 1 to 20 carbon atoms, or an alkylene group having from 1 to 20 carbon atoms which may contain therein a phenylene group; R2 represents -CO-Z4-N(Z12)-CO-Z5-H, -CO-Z6-H or a hydrogen atom, wherein Z4, Z5, and Z6 each have the same meaning as Z1, and Z12 has the same meaning as Z11; Q1 and Q2
• R1 specific examples of the groups represented by R1 are tetradecanoyl, dodecanoyl, decanoyl, N-dodecanoylglycyl, N-dodecanoylsarcosyl, 6-octanoylaminohexanoyl, 8-hexanoylaminooctanoyl, 6-benzoylaminohexanoyl, 8-benzoylaminooctanoyl, p-octanoylaminobenzoyl, 8-phenyloctanoyl, p-octylbenzoyl, and N-dodecanoyl-N-dodecylglycyl groups.
• the total carbon atoms of Z1 and Z2 are 10 to 16 and that Z3 is an acyl group having from 10 to 16 carbon atoms.
• R2 Specific examples of the groups represented by R2 are a hydrogen atom and tetradecanoyl, dodecanoyl, decanoyl, N-dodecanoylglycyl, N-dodecanoylsarcosyl, 6-octanoylaminohexanoyl, 8-hexanoylaminooctanoyl, 6-benzoylaminohexanoyl, 8-benzoylaminooctanoyl, p-octanoylaminobenzoyl, 8-phenyloctanoyl, p-octylbenzoyl, and N-dodecanoyl-N-dodecylglycyl groups.
• the total carbon atoms of Z4 and Z5 are 10 to 16 and that Z6 is an acyl group having from 10 to 16 carbon atoms.
• Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, and Z10 are phenylene (-C6H4-), methylene (-CH2-), ethylene (-CH2CH2-), tetramethylene (-(CH2)4-), pentamethylene (-(CH2)5-), hexamethylene (-(CH2)6-), heptamethylene (-(CH2)7-), nonamethylene (-(CH2)9-), undecamethylene (-(CH2)11-), dodecamethylene (-(CH2)12-) and tridecamethylene (-(CH2)13-) groups, and groups of formulae -CH2C6H4-, -(CH2)7C6H4-, and -CH2C6H4CH2-.
• the groups represented by Z11, Z12, Z13, Z14, Z15, and Z16 include phenyl-substituted or unsubstituted alkyl groups, e.g., methyl, ethyl, pentyl, heptyl, nonyl, undecyl, dodecyl, tridecyl, benzyl, 3-phenylpropyl, 5-phenylpentyl, and 7-phenylheptyl groups; alkyl-substituted or unsubstituted phenyl groups, e.g., p-hexylphenyl, p-octylphenyl, and p-decylphenyl groups; phenylene-containing or not containing alkylene groups, e.g., 7-(p-toluyl)heptyl and 3-(p-butylphenyl)propyl groups; and a hydrogen atom.
• group -OCOR11 decanoyloxy, dodecanoyloxy, tetradecanoyloxy, 8-phenyloctanoyloxy, 6-benzoylaminohexanoyloxy, N-dodecanoylglycyloxy, N-dodecanoylsarcosyloxy, 6-octanoylaminohexanoyloxy, 8-hexanoylaminooctanoyloxyr 6-benzoylaminohexanoyloxy, 8-benzoylaminooctanoyloxy, p-octanoylaminobenzoyloxy, 8-phenyloctanoyloxy, p-octylbenzoyloxy, and N-dodecanoyl-N-dodecylglycyloxy groups. Further, it is particularly preferable that the total carbon atoms of the group -OCOR
• the group -NHCOR12 are dodecanoylamino, tetradecanoylamino, N-dodecanoylglycylamino, N-dodecanoylsarcosylamino, 6-octanoylaminohexanoylamino, 8-hexanoylaminooctanoylamino, 6-benzoylaminohexanoylamino, 8-benzoylaminooctanoylamino, p-octanoylaminobenzoylamino, 8-phenyloctanoylamino, p-octylbenzoylamino, and N-dodecanoyl-N-dodecylglycyldodecanoylamino groups. Further, it is particularly preferable that the total carbon atoms of the group -NHCOR12 except for Z16 are 10 to 16.
• Y1 contains two or more substituents selected from -OCOR11 and -NHCOR12
• the moieties represented by R11 or R12 may be not be the same and may be an arbitrarily selected combination, for example, a combination of tetradecane and dodecane groups, a combination of tetradecane and dodecanoylaminomethyl groups, a combination of tetradecane, dodecane, and decane groups, and a combination of two tetradecane groups and one dodecane group.
• Y1 is an ethylene or propylene group which contains one or two substituents selected from -OCOR11 and -NHCOR12.
• the salts of the compound of formula (I) include salts with an alkali metal, e.g., sodium and potassium, an alkaline earth metal, e.g., calcium and magnesium, ammonia, an organic amine, e.g., triethylamine, pyridine, N-methylglucamine and tris(hydroxymethyl)aminomethane, etc.
• an alkali metal e.g., sodium and potassium
• an alkaline earth metal e.g., calcium and magnesium
• ammonia e.g., an organic amine, e.g., triethylamine, pyridine, N-methylglucamine and tris(hydroxymethyl)aminomethane, etc.
• the compounds of the present invention can be prepared according to the following reaction formula: wherein Q10 and Q20 each represent a protected carboxyl group or a protected phosphonoxy group; Q30 represents a protected carboxyl group, a protected phosphonoxy group or a hydrogen atom; R20 represents a hydroxyl-protective group, -CO-Z4-N(Z12)-CO-Z5-H or -CO-Z6-H; and Y1, Z4, Z5, Z6, and Z12 are as defined above.
• Protective groups for a carboxyl group include a benzyl group, etc., which may be substituted with a halogen atom, a nitro group, a lower alkoxy group, etc.
• Protective groups for a phosphonoxy group include a phenyl group, a benzyl group, etc., each of which may be substituted with a halogen atom, a nitro group, a lower alkoxy group, etc.
• Protective groups for a hydroxyl group include a benzyl group, a benzyloxycarbonyl group, etc., each of which may be substituted with a halogen atom, a nitro group, a lower alkoxy group, etc.; and a trichloroethoxycarbonyl group.
• the compound of formula (I) can be prepared by releasing the protective groups of the carboxyl and/or phosphonoxy groups and, if any, the protective group of the hydroxyl group. Removal of these protective groups may suitably be carried out by catalytic reduction of the compound of formula (II) in a solvent, such as tetrahydrofuran, methanol, ethanol, acetic acid or water, or a mixture thereof, in a hydrogen atmosphere in the presence of a catalyst, such as palladium black, palladium-on-carbon, and platinum dioxide.
• a solvent such as tetrahydrofuran, methanol, ethanol, acetic acid or water, or a mixture thereof
• a catalyst such as palladium black, palladium-on-carbon, and platinum dioxide.
• the reaction is generally conducted first by releasing the trichloroethoxycarbonyl group by treating with zinc powder in acetic acid and then releasing the other protective groups.
• the resulting compound is purified by, for example, column chromatography on silica gel and then subjected to desalting by electric dialysis, acid precipitation, a treatment with an ion exchange resin, etc.
• the compound of the present invention may be produced in the form of its salt by an appropriate method, for example, addition of a requisite amount of a base followed by precipitation or lyophilization.
• the compound of the present invention embraces a compound having an ⁇ -configuration and that having a ⁇ -configuration at the 1-position of the sugar moiety, the compound having an ⁇ -configuration exhibits superior effects in many cases.
• the starting compound of formula (II) may be prepared through route A or B shown below.
• the compound of formula (II) can be prepared by ester condensation between the primary hydroxyl group at the 6-position of compound 1 and the carboxyl group of compound 2 by an acid chloride method or a carbodiimide method, etc.
• a carbodiimide method using a condensing agent such as dicyclohexylcarbodiimide
• the reaction may be accelerated by additionally using a catalyst, e.g., 4-dimethylaminopyridine, or an active ester-forming reagent, e.g., 1-hydroxybenzotriazole.
• the compound of formula (II) wherein Y1 carries a moiety represented by -NHCOR12 may also be prepared as follows. wherein Y10 represents an alkylene group which contains at least one protected amino group and which may further contain one or more substituents selected from -OCOR11 and -NHCOR12; Y20 represents the same group as Y10, except for the protective group of the protected amino group present in Y10 has been removed; and R11 and R12 are as defined above.
• Compound 2a having a protected amino group is condensed with compound 1 in the same manner as in Route A.
• the amino-protective group of the resulting compound (IIa) is released by, for example, treating with trifluoroacetic acid or with zinc powder in acetic acid.
• the resulting compound (IIb) is then reacted with a carboxylic acid R12COOH according to an acid chloride method, a carbodiimide method, an Eintopf method, an active ester method, etc. to obtain the compound of formula (II) having -NHCOR12.
• the amino protective groups include those commonly employed in the art, e.g., a t-butoxycarbonyl group, a trichloroethoxycarbonyl group, and a methoxybenzyloxycarbonyl group.
• the starting compound 1 can be synthesized in accordance with processes reported in literature (e.g., T. Kusama et al., Chem. Pharm. Bull. , Vol. 38, p. 3366 (1990) and ibid , Vol. 39, p. 3244 (1991)) or analogous processes.
• the starting compound 2 or 2a can easily be synthesized from carboxylic acid derivatives having an amino group and/or a hydroxyl group and/or a carboxyl group, e.g., tartaric acid, glutamic acid, and serine.
• an amino-protective group e.g., a t-butoxycarbonyl group or a 2,2,2-trichloroethoxycarbonyl group, or an acyl group represented by R12CO- can be introduced to an amino-containing compound, or an acyl group represented by R11CO- or a protected phosphonoxy group can be introduced to a hydroxyl-containing compound.
• a desired compound may be obtained by protecting one of them with a benzyl group or a like protective group.
• the compounds according to the present invention exhibit an excellent activity which inhibits TNF derivation by endotoxin. Therefore, the compounds of the present invention are useful for treatment and prophylaxis of multiorganic insufficiencies.
• the compounds of the present invention can be administered orally or parenterally by, for example, injection.
• the compound of the present invention may be used at a dosage of 0.1 to 30 mg in adult human per day, though more less varying depending on the purpose of administration (therapeutic use or preventive use, etc.), and the symptoms.
• the compound of the invention can be formulated into various pharmaceutical preparations with excipients, such as stabilizers and isotonizing agents.
• excipients such as stabilizers and isotonizing agents.
• the preparations can be prepared by the conventional techniques known in the art.
• the reaction mixture was washed successively with water, 1N hydrochloric acid, and a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate.
• the catalyst was removed by filtration, and the solvent was removed from the filtrate by distillation under reduced pressure.
• the residue was dissolved in ethyl acetate and extracted with a 5% sodium hydrogencarbonate aqueous solution.
• the aqueous layer was adjusted to pH 2 to 3 with a citric acid aqueous solution and extracted with ethyl acetate.
• the extract was washed with a saturated sodium chloride aqueous solution.
• the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 4.11 g of the titled compound as a colorless oily substance.
• the oily substance (320 mg) was dissolved in 4 ml of dried methylene chloride, and 4 ml of trifluoroacetic acid was added thereto while cooling with ice, followed by stirring at the same temperature for 1 hour. The solvent was removed by distillation under reduced pressure. To the residue was added toluene, followed by distillation under reduced pressure. Toluene addition and solvent removal by distillation were repeated to obtain an oily substance.
• the oily substance (496 mg) was dissolved in 5 ml of dried methylene chloride, and 3 ml of trifluoroacetic acid was added thereto while cooling with ice, followed by stirring at the same temperature for 1 hour. The solvent was removed by distillation under reduced pressure. To the residue was added toluene, followed by distillation under reduced pressure. Toluene addition and solvent removal by distillation were repeated to obtain an oily substance.
• the solvent was removed by distillation under reduced pressure, and the residue was dissolved in dioxane and lyophilized to obtain 177 mg of the titled compound as a white powder.
• the product had a vague melting point and became caramel-like at around 125 to 130°C.
• the catalysts were removed by filtration, and the solvent was removed by distillation under reduced pressure.
• the solvent was removed by distillation under reduced pressure, and the residue was dissolved in dioxane and lyophilized to obtain 117 mg of the titled compound as a white powder.
• the product had a vague melting point and turned brown at about 145°C.
• the desired compound obtained was dissolved in a mixed solvent of tetrahydrofuran and water (9:1), and the solution was passed through a column packed with a strongly acidic ion exchange resin "Dowex 50W-X2" (H+ type). The solvent was removed from the effluent by distillation under reduced pressure, and the residue was suspended in dioxane and lyophilized to obtain 112 mg of the titled compound as a white powder.
• Example 6 The compound obtained in Example 6, Step 1 was reacted with 6-benzoylaminohexanoic acid in the same manner as in Example 5, Step 2 to obtain the titled compound as a white powder.
• Melting point: 97-101°C [ ⁇ ] 25 D : +26.4° (c 0.9, chloroform)
• Step 1 The compound obtained in Step 1 above was reacted in the same manner as in Example 1.
• the resulting oily substance was dissolved in 15 ml of dried methylene chloride, and 0.50 g of 8-benzoylaminooctanoic acid was added thereto. After once cooling with ice, 0.39 g of dicyclohexylcarbodiimide and 20 mg of dimethylaminopyridine were added thereto, followed by stirring at room temperature for 14 hours. The precipitated insoluble matter was removed by filtration, and the filtrate was washed successively with 1N hydrochloric acid, a 5% sodium hydrogencarbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate.
• the solvent was removed by distillation under reduced pressure, and the residue was purified by column chromatography on silica gel (developing solvent: 5% acetone-containing chloroform, changed en route to 2% methanol-containing chloroform) to obtain 1.162 g of the titled compound as a colorless, viscous and oily substance.
• the product was dissolved in 8 ml of dried dimethylformamide, and 0.88 ml of triethanolamine and 0.75 ml of benzyl bromide were added thereto. The mixture was heated to 50 to 60°C and stirred at that temperature for 1.5 hours. The solvent was removed by distillation under reduced pressure, and the residue was dissolved in ethyl acetate, washed successively with 1N hydrochloric acid, water, and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate.
• the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: 2% methanol-containing chloroform, changed en route to 5% methanol-containing chloroform) to obtain 465 mg of the titled compound as a colorless caramel-like semisolid.
• the resulting oily substance was dissolved in 10 ml of dried methylene chloride, and 75 ⁇ l of pyridine, 5 mg of dimethylaminopyridine, and 230 mg of tetradecanoyl chloride were successively added thereto under ice-cooling, followed by stirring at that temperature for 3 hours. Further, 0.31 mg of pyridine and 300 mg of the same acid chloride were added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was washed successively with 1N hydrochloric acid, water, and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure.
• the oily residue was dissolved in 30 ml of a 90% acetic acid aqueous solution and stirred at 90°C for 30 minutes. After cooling, the solvent was removed by distillation under reduced pressure. Toluene was added to the residue and then removed by distillation under reduced pressure. Toluene addition and removal were repeated, and the residue was purified by silica gel column chromatography (developing solvent: 5% acetone-containing chloroform, changed en route to 2% methanol-containing chloroform). Hexane was added to the product to solidify, followed by filtration to recover 633 mg of the titled compound as a white powder.
• the compound obtained in Step 2 above was reacted in the same manner as in Example 1.
• the reaction mixture was neutralized with anhydrous potassium carbonate while stirring, washed successively with water and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate.
• the solvent was removed by distillation under reduced pressure.
• the resulting yellow oily substance was dissolved in 20 ml of dried methylene chloride, and 0.40 ml of pyridine, 0.61 g of N,N-dimethylaminopyridine, and 0.71 ml of benzyloxycarbonyl chloride were successively added thereto at room temperature, followed by stirring at room temperature for 12 hours.
• the reaction mixture was washed successively with 1N hydrochloric acid, water, and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate.
• the solvent was removed by distillation under reduced pressure.
• the resulting yellow oily substance was dissolved in 50 ml of a 90% acetic acid aqueous solution, and the solution was stirred at 90°C for 30 minutes. After cooling, the solvent was removed by distillation under reduced pressure. Toluene was added to the residue and then removed by distillation under reduced pressure.
• Step 1 The compound obtained in Step 1 above was reacted in the same manner as in Example 8, Step 2 to obtain the titled compound as a white powder.
• Example 6 The compound obtained in Example 6, Step 1 was reacted with 8-phenyloctanoic acid in the same manner as in Example 5, Step 2 to obtain the titled compound as a white powder.
• Melting Point: 68-70°C [ ⁇ ] 25 D : +25.3° (c 2.2, chloroform)
• Monocytes (5.0 ⁇ 104/well) isolated from a heparin-added blood sample (taken from a healthy person) by means of a specific gravity separatory liquid were used. Monocytes were cultured for 4 hours in a 10% fetal bovine serum-added RPMI-1640 medium (0.5 ml/well) to which 0, 1, 10 or 100 ng/ml of LPS ( E . coli 0127:B8, DIFCO) and 0.5, 5 or 50 ng/ml of a test compound had been added. The TNF activity of the supernatant liquid of the culture was determined by a cytotoxic test against L929 cells. The results obtained are shown in Table 3 below. TABLE 3 Test Compound No. Concn.
• the compounds of the present invention are of low toxicity.
• Compound Nos. 1 to 3 when each of Compound Nos. 1 to 3 was intravenously injected to the tail of mice, no abnormality was observed at a level of 200 ⁇ g/mice.

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• 1993
  • 1993-03-29 NO NO931167A patent/NO178729C/no unknown
  • 1993-03-30 AU AU35608/93A patent/AU658277B2/en not_active Ceased
  • 1993-03-30 FI FI931425A patent/FI931425A/fi not_active Application Discontinuation
  • 1993-03-30 CA CA002092971A patent/CA2092971A1/en not_active Abandoned
  • 1993-03-30 EP EP93105296A patent/EP0563908A1/de not_active Withdrawn
  • 1993-03-31 KR KR1019930005241A patent/KR930019687A/ko not_active Application Discontinuation
  • 1993-03-31 US US08/040,987 patent/US5432267A/en not_active Expired - Fee Related
  • 1993-03-31 CN CN93105211A patent/CN1081681A/zh active Pending

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